tbuckley/cabot-search huggingface dataset:
Abstract 5852: Vimentin content associated with shear wave speed in hepatocellular carcinoma: Non-invasive identification of more aggressive tumor phenotypes
Authors: Andrea C. Cortes, Kiyoyuki Minamiguchi, Patricia L. Da Costa Lopez, Simone Anfossi, Williams Malea L, Maria S. Stenkamp, Rony Avritscher, Natalie W. Fowlkes
Journal: Cancer Research (2023)

Abstract Tumor stromal heterogeneity can negatively impact immune surveillance and treatment outcomes. Current cross-sectional imaging tools rely solely on tumor size and perfusion to monitor therapy and fail to characterize tumor biomechanics. Shear-wave elastography has emerged as a non-invasive technique that can quantify stromal elasticity. The goal of the present study is to characterize the molecular underpinnings associated with shear wave elastography measurements in liver cancer. To this end, rat hepatoma cell line McA-RH7777 stably expressing green fluorescent protein genes (fluc/GFP) were implanted in the left liver lobe of Buffalo rats. Three weeks after tumor implantation, adequate tumor size was verified by B-mode ultrasound. A 7-color panel was developed to assess the percentage of vimentin, α-smooth muscle actin, IBA-1, S100A4, TGF-β, and glial fibrillary acidic protein (GFAP) in tumor sections. Shear wave elastography data was used to stratify tumor nodules as stiff or soft according to the mean value of the shear wave (3.05 versus 2,26 m/s). Our results showed two distinct tumor phenotypes. Stiffer tumors, as determined by higher shear wave speed measurements on ultrasound, were characterized by higher percentages of vimentin-positive cells, low S100A4 and IBA-1 macrophages expressing TGF-b, and intermediate expression of IBA-1 macrophages and GFAP cells. Slow shear wave speed, characteristic of softer tumors, displayed the opposite phenotype (two-factor ANOVA; P≤0.001). The most remarkable difference between stiffness phenotypes was the percentage of cells expressing vimentin, with a mean percentage in stiffer tumors of 26.54 compared with 13.68% in softer tumors (P&amp;lt;0.003). Our results indicate that high expression of vimentin is highly correlated with increased shear wave speeds. Given the association between vimentin expression and epithelial-mesenchymal transition a marker of aggressive characteristics of tumor cells (increased migration and invasion), our findings suggest that longitudinal quantification of shear wave speed can be useful to assess functional changes in the stromal component and identify more aggressive tumor phenotypes with a higher likelihood of metastatic potential. Citation Format: Andrea C. Cortes, Kiyoyuki Minamiguchi, Patricia L. Da Costa Lopez, Simone Anfossi, Williams Malea L, Maria S. Stenkamp, Rony Avritscher, Natalie W. Fowlkes. Vimentin content associated with shear wave speed in hepatocellular carcinoma: Non-invasive identification of more aggressive tumor phenotypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5852.
Abstract 3224: TTFields-prolonged the PFS of epithelioid glioblastoma patient: a case report
Authors: Yuxuan Ding, Qiang Wang, Feijiang Wang, Nan Wu, Jianrui Li, Xia He, Hao Pan, Lijun Wang
Journal: Cancer Research (2023)

Abstract Epithelioid glioblastoma (EGBM, classified as glioblastoma, wild type, grade IV according to 2021 WHO CNS5 classification of neurological malignancies) is a highly aggressive malignancy, the median progression-free survival (mPFS) of which is about 4.0 months. Although, the introduction of tumor treating fields (TTFields, possessing anti-cancer capability via anti-mitotic effects) in the maintenance of TMZ chemotherapy was demonstrated beneficial for prolonging the mPFS of GBM patients to 6.9 months in the EF-14 clinical trial, studies centering on the significance of TTFields in EGBM treating are very limited due to the rarity of EGBM. Therefore, a 28-year-old patient (male, recurrent left-sided limb twitching for 1 month and dizziness for 1 week) was chosen as a clinical trial participant. A right frontal lobe occupancy was detected based on magnetic resonance imaging (MRI), and total tumor resection was performed on the patient. Meanwhile, postoperative histopathology test, including immunohistochemical and molecular characterization, was conducted and the results revealed a BRAF V600E mutation, no codeletion of 1p and 19q, and negative MGMT promoter methylation, which confirmed EGBM. In this context, chemoradiotherapy was conducted on the patient at first, and then concurrent TTFields and TMZ was performed. Notably, a long-term PFS of 33 months and KPS score of 90 were achieved over the patient upon TTFields combined TMZ, whose average daily usage of TTFields was higher than 90%. This clinical case corroborated the importance of TTFields in EGBM treating, and the higher compliance of TTFields is more beneficial for EGBM patient without additional side effect. YD, QW contributed equally to this work. Citation Format: Yuxuan Ding, Qiang Wang, Feijiang Wang, Nan Wu, Jianrui Li, Xia He, Hao Pan, Lijun Wang. TTFields-prolonged the PFS of epithelioid glioblastoma patient: a case report [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3224.
Abstract 5968: Leukemia inhibitory factor regulates macrophage immune response in head and neck squamous cell carcinoma
Authors: Yun Hua Sui, Tzu Tung Liu, Shu Chen Liu
Journal: Cancer Research (2023)

Abstract The high recurrence rate of head and neck squamous cell carcinoma (HNSCC) is associated with an immune suppressive tumor microenvironment (TME). Tumor-associated macrophage (TAM)-mediated immunosuppression is a critical feature in HNSCC TME. We provide evidence demonstrating that leukemia inhibitory factor (LIF) is involved in macrophage polarization and remodeling of the HNSCC microenvironment. By interrogating the head and neck squamous cell carcinoma RNA sequencing dataset extracted from the TCGA database, we found that the levels of LIF and M2 macrophage markers (CD163, CD206, VEGF) were enhanced in tumors compared to normal counterparts. Higher LIF expression in tumors was further correlated with worse overall survival. Immunohistochemical analysis found that macrophages with higher LIF immunoreactivities were located at the periphery of HNSCC tumors. In a macrophage-cancer cell coculture system, the presence of LIF promoted the proliferation and mobility of cancer cells and induced an M2-dominant macrophage polarization. Stimulating monocyte-derived macrophages (MDMs) with LIF increased the expression of several M2 markers (CD163, CD206, CD209, and IL10) but decreased the expression of M1 markers (iNOS, CD80, and CD86). Moreover, LIF-treated macrophages exhibited little cancer cytotoxicity compared to vehicle-treated macrophages. Treating macrophages with soluble LIF receptor (sLIFR), a LIF antagonist, partly reversed the LIF-mediated M2 polarization and enhanced cytotoxicity toward cancer cells. Results of RNA-sequencing data demonstrated that LIF suppressed antigen presentation process, type I interferon production, TNFR signaling, and molecules participating in the Hippo signaling pathway in MDMs. Mechanistic studies found that LIF might trigger M2 polarization via activating YAP1, as reflected by a reduction of p-YAP1 (S127) and an enhanced YAP1 nuclear localization in macrophages. Treating macrophages with YAP1 inhibitors (Saracatinib and Verteporfin) blocked the LIF-mediated YAP1 nuclear translocation, expression of M2 markers, and tumor-promoting effects. Our findings suggest that the presence of LIF in HNSCC promotes macrophage M2 polarization through YAP1 signaling, which assists in establishing an immune-suppressive, tumor-promoting microenvironment. The blockade of LIF-mediated effects may tailor therapeutic strategies by converting the immunosuppressive microenvironment for selected HNSCC patients. Citation Format: Yun Hua Sui, Tzu Tung Liu, Shu Chen Liu. Leukemia inhibitory factor regulates macrophage immune response in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5968.
Abstract 4819: Mechanism of disturbance of nuclear size homeostasis in cancer cells
Authors: Changgon Kim, Joon Kim
Journal: Cancer Research (2023)

Abstract Abnormal increase in nuclear size is one of the criteria for distinguishing cancer cells. The main causes and functional consequences of nuclear size increase in cancer cells are not well known. In this study, we analyzed genome-wide RNAi library screen data to discover genes involved in the maintenance of nuclear size homeostasis. Importantly, many of the screen hits mapped to the functional categories of replication stress and DNA damage repair. We confirmed that depletion of genes required to prevent replication fork collapse causes a significant increase in nuclear size. Excessive replication stress and defects in the DNA repair system are common in many cancers. Therefore, disturbances of nuclear size homeostasis may be due to excessive replication stress and enhanced DNA damage response. To identify effectors that link replication stress and nuclear size change, we investigated candidates such as cell cycle progression, the mTOR pathway, and the cytoskeleton. As previously known, cell cycle arrest at G2 phase increased nuclear size, but replication fork collapse increased nuclear size even more excessively, suggesting the existence of other mechanisms. Inhibition of the mTOR pathway did not block replication stress-induced nuclear enlargement. Interestingly, we found that actin polymerization inside the nucleus plays a role in determining nuclear size in replication stress condition. Inhibition of nuclear actin polymerization reversed nuclear enlargement due to replication fork collapses. The Increase in nuclear size appeared to reduce the invasive ability of cancer cells. In addition, the enlarged nuclei resisted mechanical stress-mediated nuclear envelope rupture. We also observed a change in the abundance of the tri-methylation of lysine 27 on histone H3. These results suggest that nuclear size homeostasis is perturbed as a result of excessive replication stress, and changes in nuclear size affect the invasive capacity and gene expression of cancer cells. However, it is not clear whether nuclear enlargement act as a strong barrier to metastasis, as nuclear size can readily change through changes in nuclear actin dynamics. Further studies are needed to understand the impact of nuclear size changes on cancer initiation and progression. Citation Format: Changgon Kim, Joon Kim. Mechanism of disturbance of nuclear size homeostasis in cancer cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4819.
Abstract 5845: Periostin secreted by cancer-associated fibroblasts promotes cancer progression and drug resistance in non-small cell lung cancer
Authors: Mao Yoshikawa, Fumiaki Takatsu, Ken Suzawa, Tomohiro Habu, Ohki Masayoshi, Kazuma Iwata, Naoki Matsuda, Yin Min Thu, Kazuhiko Shien, Hiromasa Yamamoto, Shinichi Toyooka
Journal: Cancer Research (2023)

Abstract Background: Cancer-associated fibroblasts (CAFs) are key players in the tumor microenvironment (TME) due to their abundance in most solid tumors and active crosstalk with cancer cells, and promote the initiation of tumor formation, tumor growth, angiogenesis, metastasis, and therapeutic resistance. In this study, we sought to identify effective therapeutic targets in CAFs for non-small cell lung cancer (NSCLC). Experimental Design: We established fibroblast cell lines from the cancerous and non-cancerous parts of surgical lung specimens from patients with NSCLC and evaluated the differences in behaviors towards NSCLC cells using in vitro co-culture models, conditioned medium, and in vivo xenograft mouse models. Next, RNA sequencing analysis was performed to investigate the differentially expressed genes between normal fibroblasts (NFs) and CAFs, and we then verified the biological activity of the identified molecule on NSCLC cells in vitro and in vivo mouse model. Results: Cancer cells showed enhanced cell proliferation, migration, and drug resistance by co-culture with CAFs or CAF-derived conditioned medium. RNA sequencing analysis revealed that CAFs showed higher expressions of POSTN, a matricellular protein, than NFs. Single-cell RNA sequencing data of NSCLC from public database confirmed that POSTN-positive fibroblasts were highly enriched in lung tumor tissues but rarely observed in normal lung tissues, suggesting CAF-specific POSTN expression in lung cancer. Recombinant POSTN increased cell proliferation via NSCLC cells’ ERK pathway activation and induced epithelial-mesenchymal transition (EMT), which improved migration in vitro. In addition, POSTN knockdown in CAFs suppressed these effects, and in vivo experiments demonstrated that the POSTN knockdown improved the sensitivity of EGFR-mutant NSCLC cells for Osimertinib treatment. Conclusion: Our results showed that CAF-derived POSTN is involved in tumor growth, migration, EMT induction, and drug resistance in NSCLC. Targeting CAF-secreted POSTN in TME could be a potential therapeutic strategy for NSCLC. Citation Format: Mao Yoshikawa, Fumiaki Takatsu, Ken Suzawa, Tomohiro Habu, Ohki Masayoshi, Kazuma Iwata, Naoki Matsuda, Yin Min Thu, Kazuhiko Shien, Hiromasa Yamamoto, Shinichi Toyooka. Periostin secreted by cancer-associated fibroblasts promotes cancer progression and drug resistance in non-small cell lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5845.
Abstract 251: Identification of therapeutic vulnerabilities by genome-wide CRISPR knockout library screening of colon cancer organoids
Authors: Phillip J. Buckhaults, Sana Khalili, Carolyn Banister, Prashanth R. Gokare, Dave Pocalyko, Kurtis Bachman
Journal: Cancer Research (2023)

Abstract The promise of precision medicine is based on the idea that genetic alterations present only in tumor cells create vulnerabilities that can be targeted for therapeutic intent. In some instances, somatically mutated driver genes such as KRAS, BRAF or PIK3CA can be targeted with small molecule inhibitors specific for mutant oncoproteins. In other cases therapeutic vulnerability is an indirect consequence, such as response to immune checkpoint inhibitors caused by somatic inactivation of mismatch repair genes and subsequent creation of neo-antigens in tumors. Synthetic lethal vulnerabilities dependent on common somatic alterations would be highly specific therapeutic targets applicable to a large number of cancer patients. We sought to identify potential therapeutic vulnerabilities for colon cancer by performing a genome wide CRISPR knockout screen in a colon cancer organoid in both TP53-Wild-Type and TP53-Knockout backgrounds. We identified 1784 gene knockouts with TP53-dependent effects on Darwinian fitness. Examples include MDM2 and PPM1D knockouts, both of which selectively harmed the TP53 WT organoids. 250 gene knockouts selectively harmed the TP53 KO organoids and represent novel avenues for development of TP53 synthetic lethal targeted therapeutics. We also identified ~1000 gene knockouts under significant negative Darwinian selection in both TP53 WT and TP53 KO organoids which are not known to be common essential genes. Several of these organoid model specific vulnerabilities are in pathways that are downstream of the somatic mutations present in the tumor and are therefore candidates for highly-specific targeted therapeutic intervention. Examples include Werner’s pathway dependencies (WRN, EME1, MUS81) which are known to result from mismatch repair deficiency, WNT pathway dependencies (CTNNB1, PORCN) which result from RNF43 inactivating somatic mutation, and BRAF dependency resulting from its own activating oncogenic somatic mutation. In summary, genome-wide CRISPR knockout library screening of human colon cancer organoids can provide a comprehensive overview of dependencies interacting with either natural or engineered mutations and are a promising novel platform for discovering personalized or pathway based therapeutic targets. Future work will focus on target validation and additional primary screens using our biobank of tumor-normal organoid pairs. Citation Format: Phillip J. Buckhaults, Sana Khalili, Carolyn Banister, Prashanth R. Gokare, Dave Pocalyko, Kurtis Bachman. Identification of therapeutic vulnerabilities by genome-wide CRISPR knockout library screening of colon cancer organoids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 251.
Abstract 1760: ADI-PEG20 and GC7 as a novel anti-metabolite strategy for the treatment of malignant pleural mesothelioma
Authors: Joséphine Carpentier, Peter W. Szlosarek, Sarah Anne Martin
Journal: Cancer Research (2023)

Abstract Malignant pleural mesothelioma (MPM) is a highly aggressive cancer with less than 10% of patients surviving 5-years from diagnosis. Arginine deprivation using pegylated arginine deiminase (ADI-PEG20) is a novel treatment for mesothelioma deficient in the arginine biosynthetic enzyme ASS1. However, resistance to ADI-PEG20 in MPM is a significant problem and is characterized in part by reprogramming of the urea and polyamine metabolism pathway (Locke et al., 2016). We sought to identify a targeted metabolism-based therapy to overcome the emerging resistance and increase the efficiency of ADI-PEG20 treatment for patients with MPM. New models of ADI-PEG20 resistance were generated by constant exposure of MPM cell lines to arginine deprivation for 6 months. ADI-PEG20 resistant and sensitive MPM cell lines were treated with a panel of polyamine targeting molecules. Metabolome alterations were studied by targeted metabolomics and glucose flux analyses. Our results confirmed the up-regulation of ASS1 expression from (50 to 3000-fold) alongside upregulation of polyamine catabolism and upon generation of ADI-PEG20 resistance. Treatment of ADI-PEG20 resistant cell lines with a range of different polyamine inhibitors demonstrated that ADI-PEG20 resistant cell lines were significantly more sensitive to the spermidine-analogue GC7 than their respective ASS1-ve parental cell lines. Moreover, the combination of GC7 and ADI-PEG20 prevented the emergence of resistant cells in vitro. We observed a significant synergistic effect of GC7 and ADI-PEG20 in both ASS1-ve and ASS1+ve cell lines in 2D and 3D cell culture models as well as in our mice in vivo model. Metabolomics analysis revealed that GC7 treatment significantly impaired the TCA cycle. We hypothesize that GC7 is repurposing the fate of Acetyl-CoA to polyamine catabolism therefore shutting down the TCA cycle. Our findings provide novel insights into a polyamine targeted therapy that may prevent resistance to ADI-PEG20 treatment in MPM and related arginine-auxotrophic cancers. Citation Format: Joséphine Carpentier, Peter W. Szlosarek, Sarah Anne Martin. ADI-PEG20 and GC7 as a novel anti-metabolite strategy for the treatment of malignant pleural mesothelioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1760.
Abstract 3543: Mesenchymal stromal cells and tumor-associated macrophages modulate adrenergic to mesenchymal state switching in neuroblastoma
Authors: Meng-Hua Lee, Kevin Louault, Krinio Giannikou, Xiangming Ding, Alice Yanovsky, Jin-Seok Park, Yves A. DeClerck, Shahab Asgharzadeh
Journal: Cancer Research (2023)

Abstract Neuroblastoma (NB), a common solid tumor of children, can adopt a lineage-committed adrenergic (ADRN) or an immature mesenchymal (MES) tumor cell type, which differs in phenotype, epigenetic landscape, transcription factors, and core regulatory circuitries. These cell types can spontaneously interconvert, but the mechanism remains largely unknown. Here, we hypothesize that the tumor-associated macrophages (TAM) and cancer-associated fibroblast (CAF) within the tumor microenvironment contribute to pro-tumorigenic factors production and drive switching from ADRN to MES state in neuroblastoma. We first demonstrate the ADRN and MES lineage identity of NB cell lines by Western blot and compared the control and NB cell lines co-cultured with mesenchymal stromal cells (MSC), the precursor cell of CAF, and monocyte in transwell. Initial experiments demonstrated the morphology of NB cell line CHLA255 and CHLA136 showing increased spreading area and spindle shape in TAM-CAF co-cultures compared to control cells. As compared to control cells, monocytes and MSC-CAF co-culture induced the MES lineage markers SOX9 and Notch1 of NB cell lines that had low basal SOX9 expression, with a reduction in protein levels of ADRN lineage markers PHOX2B, and GATA3. Next, single-cell RNA-sequencing was utilized to analyze the expression of TAM and CAF, and MES- and ADRN-signature genes of NB cells in NB-TAM-CAF co-cultures. Single-cell analyses of TAM-CAF co-cultured CHLA255 and CHLA136 demonstrated enrichment of MES signature over time providing clear evidence of mesenchymal differentiation of NB cells within a TME-rich environment. Pathway enrichment analyses reveal enrichment of pathways associated with extracellular matrix (ECM) deposition and epithelial to mesenchymal of TAM-CAF co-cultured NB cell lines. Our results suggested that the presence of CAF and TAM in the tumor microenvironment drives neuroblastoma ADRN: MES switch akin to that observed in epithelial: mesenchymal switch in adult tumors. ADRN-MES state switching has been shown relevant for tumor relapse and therapy resistance. Our studies point to a therapeutic vulnerability by targeting cells and pathways activated in the NB-TAM-CAF axis. Citation Format: Meng-Hua Lee, Kevin Louault, Krinio Giannikou, Xiangming Ding, Alice Yanovsky, Jin-Seok Park, Yves A. DeClerck, Shahab Asgharzadeh. Mesenchymal stromal cells and tumor-associated macrophages modulate adrenergic to mesenchymal state switching in neuroblastoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3543.